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Immune system J. Ochotná

The main functions of the immune system Immune system belongs to the basic homeostatic mechanisms Defense Autotolerance Immune surveillance

Antigen (immunogen) * substance that can induce a humoral and/or cell-mediated immune response * predominantly proteins or polysaccharides * molecules >5 kDa (optimal size of antigen is about 40 kDa) * autoantigen * exoantigen * allergen

Haptens * small molecules, that are able to induce specific immune response only after the establishment to the macromolecular carrier (separate haptens are not immunogenic) * typically drugs (eg penicillin antibiotics, hydralazin)

Interaction antigen – antibody Interaction antigen – antibody * Binding site of antibody (paratop) form non-covalent complexes with the corresponding part on antigen molecule (epitope) * antigen-antibody complex is reversible

Types of antigens according to antigen presentation 1) thymus dependent antigens * more frequent, especially protein Ag * for induction of humoral immune response is necessary cooperation with TH cells (or response isn´t enough effective) * assistance implemented in the form of cytokines produced by TH cells

Types of antigens according to antigen presentation 2) thymus independent antigens * can induce antibodies production directly without the participation of T lymphocytes * mainly bacterial polysaccharides, lipopolysaccharides and polymer forms of proteins (e.g. Haemophilus, Str.pneumoniae) T-independent pathway

Superantigens. stimulate lymphocytes polyclonaly and massively (5-20%) Superantigens * stimulate lymphocytes polyclonaly and massively (5-20%) * massive activation of T lymphocytes can cause shock * e.g. bacterial toxins (Staph.aureus, Str.pyogenes, Pseud.aeruginosa)

Sequestered antigens * autoantigens that are normally hidden from the immune system and therefore unknow (e.g. the lens of the eye , testes, brain) * if they are "uncovered" by demage, can induce the immune response (one of the theories of autoimmune processes)

Components of the immune system

Components of the immune system * Lymphoid tissues and organs * Cells of the immune system * Molecules of the immune system

Lymphoid tissues and organs * are linked with the other organs and tissues by network of lymphatic and blood vessels Primary lymphoid tissues and organs * bone marrow, thymus * maturation and differentiation of immunocompetent cells * immature lymphocytes acquire here their antigenic specificity

Secondary lymphoid tissues and organs * meeting place of immunocompetent cells with Ag spleen - filters the blood and captures presented antigens lymph nodes and their organized clusters (tonsils, appendix, Peyer patches in the intestine) - filter lymph and capture present antigens MALT (mucous associated lymphoid tissue) - diffuse lymphatic tissue, the main role is capture of antigens passing through the mucosal epithelium

Cells of the immune system Cells of the immune system * development of red and white blood cells begin at yolk sack, then haematopoiesis travels to fetal liver and spleen (3 to 7 month gestation), then bone marrow has the main hematopoietic function * all blood cells arise from a pluripotent stem cell (CD 34) * haematopoiesis is regulated by cytokines

Immune mechanisms

Nonspecific (innate) immune mechanisms. non-adaptive, innate Nonspecific (innate) immune mechanisms * non-adaptive, innate * evolutionarily older * no immunological memory * in the presence of pathogens react quickly, in minutes (based on molecules and cells which are in the body prepared in advance) * component cellular – granulocytes (neutrophils, eosinophils, basophils), monocytes (macrophages, DC), NK cells, mast cells humoral - complement, interferons, lectins and other serum proteins

Specific (adaptive) immune mechanisms. adaptive, antigen-specific Specific (adaptive) immune mechanisms * adaptive, antigen-specific * evolutionarily younger * have immunological memory * development of a full-specific immune response takes several days even weeks * component cellular - T lymphocytes (TCR) humoral - antibodies

Phagocytosis

Phagocytosis = ability to absorb particles from the surroundings Professional phagocytes * cells, which provide defenses by mechanism of phagocytosis * neutrophilic granulocytes, monocytes, macrophages and DC

Professional phagocytes granulocytes - defense against extracellular pathogens - able to perform effector functions immediately macrophages - removal of own apoptotic cells, defense against certain intracellular parasites, APC - fully functional after activation by cytokines (IFNg, TNF) Macrophage

The migration of phagocytes in damaged and infected tissues 7% of peripheral neutrophils and phagocytes 93% neutrophils and phagocytes in the bone marrow * in place of damage phagocytes are captured on endothelium (due to inflammatory cytokine expression of adhesion molecules is higher)

Phagocytosis * the first interactions with adhesion molecules slows the movement of neutrophils - roling * then there is a stronger link between endothelial cells and leukocytes and subsequent penetration between endothelial cells to the tissue - diapedesis (or extravasation) * phagocytes direct their movement to the site of inflammation by chemokines (IL-8, MIP-1a and b, MCP-1, RANTES, C3a, C5a, bacterial products ...)

Receptors on phagocytes PAMPs (pathogen associated molecular patterns) PRR (pathogen recognition receptors) * TLR receptors (binds bacterial lipoproteins, lipopolysaccharides, bacterial DNA) * mannose receptor * galactose receptor * CD14 (binds bacterial LPS) * scavenger receptors (bind phospholipids on the surface of apoptotic cells)

Opsonisation * is the process by which a pathogen is marked for ingestion and destruction by phagocyte * Opsonins - IgG, IgA, C3b, MBL, fibronectin, fibrinogen, CRP, SAP * Fc receptors on phagocytes (recognize antibodies linked to surface of micro-organism) * complement receptors (for binding C3b)

Phagocytosis

Degradation of ingested material Degradation of ingested material * fagosome fusion with lysosomes - oxygen independent (lysozyme, defensines, serine proteases, myeloperoxidase, acidic pH…) * activation of membrane NADPH oxidase - oxygen dependent (superoxide, hydrogen peroxide, hypochlorous acid) * production of nitric oxide (NO) by macophages

Secretory products of phagocytes Secretory products of phagocytes * IL-1, 6, TNF (systemic response to inflammation) * IL-8 (chemokine) * IL-3, GM-CSF (control haematopoiesis) * TGFa, TGFb (tissue regeneration) * metabolic products of arachidonic acid (prostaglandins, prostacyclin, leukotrienes and thromboxanes)

Complement

Complement * system of about 30 serum and membrane proteins * complement components are present in the serum in inactive form * complement activation has cascade character * complement proteins are synthesized in the liver, less by tissue macrophages and fibroblasts * the main complement components: C1-C9 (C3 is the central component) * other complement components: factor B, factor D, factor P * regulatory proteins: C1 - inhibitor, factor I, factor H, DAF, MCP, CR1, CD59 (protektin) inactivator of anafylatoxin…

Complement functions * Opsonization (C3b) * Chemotaxis (C3a, C5a) * Osmotic lysis (MAC C5b-C9) * Anafylatoxins (C3a, C4a, C5a)

Complement activation * Alternative pathway * Clasial pathway * Lektin pathway

Regulation of complement and protection of own cells Activation of complement cascade is controlled by the plasma and membrane inhibitors. Anaphylatoxin inactivator DAF Protectin MCP

Complement regulation C1 inhibitor (C1-INH) – inhibits C1; if missing→ HAE factor I with cofactors: MCP (membrane cofactor protein), CR1, factor H – C3b, C4b cleavage DAF (decay-accelerating protein)-degradation of C3 and C5 convertase

Complement regulation factor S (vitronectin) – inhibits complex C5bC6 CD 59 (protectin) - prevents the polymerization of C9 anaphylatoxin inactivator (CPN)- inactivates anafylatoxins (C3a, C4a, C5a)

Complement receptors * Bind fragments of complement components CR1 - on various cells - removing of immunecomplexes CR2 - on B lymphocytes and FDC - activation of B cells CR3, CR4 - on phagocytes - participation in opsonization, adhesion

Basophils and mast cells and their importance in immune responses

Mast cells Mucosal mast cells - in the mucous membranes of respiratory and gastrointestinal tract, participate in parasitosis and allergy Connective tissue mast cells - the connective tissue, in parasitosis and allergy are not participating

Mast cell functions Defense against parasitic infections Responsible for the early type of hypersensitivity (allergic reaction) Apply during inflammation, in angiogenesis, in tissue remodeling Regulation of immune response

Mast cell activation Mast cells degranulation can be stimulated by: cross-linking of IgE Fc receptors anafylatoxins (C3a, C4a, C5a) TLR

Mast cell activation by cross-linking of IgE Fc receptors Establishing of multivalent antigen (multicellular parasite) to IgE linked to highaffinnity Fc receptor for IgE (FcRI) Aggregation of several molecules FcRI Initiate mast cell degranulation (cytoplasmic granules mergers with the surface membrane and release their contents) Activation of arachidonic acid metabolism (leukotriene C4, prostaglandin D2) Production of cytokines (TNF, TGF, IL-4, 5,6 ...)

Activation schema of mast cell

Secretory products of mast cells Cytoplasmatic granules: hydrolytic enzymes, heparin, chondroitin sulphate, histamine, serotonin Arachidonic acid metabolites (leukotriene C4, prostaglandin D2) Cytokines (TNF, TGF , IL-4, 5,6 ...)

Histamine vasodilation increased vascular permeability bronchoconstriction increases intestinal peristalsis increased mucus secretion

Basophils Differentiate from myeloid precursor Are very similar to mast cells by the receptor equipment, content of granules, the mechanisms of stimulation and functions Play role in inflammation, regulation of immune responses, in allergic reactions, they are responsible for the emergence of anaphylactic shock In high numbers at the sites of ectoparasite infection

Complement – clasical pathway https://www. youtube. com/watch Complement – alternative pathwayhttps://www.youtube.com/watch?v=qga3Wn76d9w Complement https://www.youtube.com/watch?v=5Ao36HNvwvw Immune reaction https://www.youtube.com/watch?v=G7rQuFZxVQQ